APNEA AND CONTROL OF BREATHINGCHRISTA MATRONE, M.D., M.ED.

DIOMEL DE LA CRUZ, M.D.

OBJECTIVES

¢ Define Apnea

¢ Review Causes and Appropriate Evaluation of Apnea in Neonates

¢ Review the Pathophysiology of Breathing Control and Apnea of Prematurity

¢ Review Management Options for Apnea of Prematurity¢ The Clinical Evidence for Caffeine

¢ The Role of Gastroesophageal Reflux

DEFINITION OF APNEA

¢ Cessation of breathing for greater than 15 (or 20) seconds

¢ Or if accompanied by desaturations or bradycardia

¢ Differentiate from periodic breathing

¢ Regular cycles of respirations with intermittent pauses of >3 S

¢ Not associated with other physiologic derangements

¢ Benign and self-limiting

TYPES OF APNEA

CENTRAL

¢ Total cessation of inspiratory effort

¢ Absence of central respiratory drive

OBSTRUCTIVE ¢ Breathing against an obstructed airway

¢ Chest wall motion without nasal airflow

MIXED¢ Obstructed respiratory effort after a central pause

¢ Accounts for majority of apnea in premature infants

APNEA IS A SYMPTOM, NOT A DIAGNOSIS

Martin RJ et al. Pathogenesis of apnea in preterm infants. J Pediatr. 1986; 109:733.

APNEA IN THE NEONATE: DIFFERENTIAL

Central Nervous System Respiratory

• Intraventricular Hemorrhage• Seizure• Cerebral Infarct

• Airway Obstruction• Inadequate Ventilation / Fatigue• Hypoxia

Infection Gastrointestinal

• Sepsis• Meningitis

• Necrotizing Enterocolitis• Gastroesophageal Reflux

Hematologic Drug Exposure

• Anemia• Polycythemia

• Perinatal (Ex: Magnesium, Opioids)• Postnatal (Ex: Sedatives, PGE)

Cardiovascular Other

• Patent Ductus Arteriosus • Temperature instability• Metabolic derangements

APNEA IN THE NEONATE: EVALUATION

¢ Detailed History and Physical Examination¢ Gestational age, post-natal age, and birth history

¢ Other new signs or symptoms

¢ Careful attention to neurologic, cardiorespiratory, and abdominal exam

APNEA IN THE NEONATE: EVALUATION

¢ Laboratory Studies

¢ CBC/diff and CRP

¢ Cultures, consideration of LP

¢ Electrolytes including magnesium

¢ Blood gas and lactate

¢ Radiologic Studies

¢ Head ultrasound vs. MRI

¢ Chest and/or abdominal films

¢ Cardiac studies (EKG, echo)

APNEA OF PREMATURITY

¢ Apnea of Prematurity (AOP) is a diagnosis of exclusion

¢ Peak onset is at 5-7 days of post-natal age

¢ The likelihood of AOP increases with decreasing gestational age and weight

¢ The pathophysiology of AOP is multifactorial ¢ Understanding is extrapolated from basic science and animal models

RESPIRATORY HOMEOSTASIS

Medullary and Pontine Respiratory

Centers

Central Chemoreceptors

Peripheral Chemoreceptors

Carotid Body

Laryngeal Chemoreflex

Mechanoreceptors

Pulmonary Stretch Receptors

Pharyngeal Afferents

Output to Muscles of RespirationExcitatory or Inhibitory

CHEMICAL CONTROL OF BREATHING

Chemical Control of Breathing

Peripheral CO2 Sensitivity (carotid body)

Hypoxic Chemosensitivity

(carotid body)

Genetic Regulation

Central CO2 Sensitivity

(ventrolateral medulla)

CENTRAL CHEMORECEPTORS

¢ Central Chemoreceptors

¢ Located on ventral medulla

¢ Detects changes in CSF pH

¢ Sensitive to CO2 and H+

¢ Maintain CO2 and pH in narrow physiologic range

THE CAROTID BODY

¢ Carotid Body

¢ Primary peripheral chemoreceptor

¢ Sensitive primarily to hypoxia

¢ Can also detect changes in CO2, pH, temperature

¢ Hypoxia triggers increase in minute ventilation

MECHANICAL CONTROL OF BREATHING

Mechanical Control of Breathing

Sensory Input from Upper Airway

Pulmonary Stretch Receptors

DYSREGULATION IN THE NEONATE

Apnea of prematurity

Decreased response to hypercapnia

Enhanced inhibitory responses

Hypoxic respiratory depression

Upper airway

collapse

RESPONSE TO HYPERCAPNIA

Gerhardt T, et al. Apnea of prematurity: I. Lung function and regulation of breathing. Pediatrics. 1984; 74:58.

RESPONSE TO HYPOXIA

¢ Abnormal biphasic response to hypoxia

¢ Initial increase in ventilation followed by a decline

¢ Likely represents depression of central respiratory center due to hypoxia

¢ Theoretical role of ‘Diving Reflex’ in bradycardia

¢ In diving mammals, results in bradycardia during episodes of hypoxia

¢ ‘Diving Reflex’ persistent in humans until around 6 months of age

VENTILATORY RESPONSE TO 15% FIO2 HYPOXIA IN PRETERM INFANTS

Martin RJ, et al. Persistence of the biphasic ventilator responses to hypoxia in preterm infants. J Pediatr. 1998;132:960.

INITIATION OF BREATHING AFTER RESUSCITATION OF RAT PUPS

Bookatz GB et al. Effect of Supplemental Oxygen on Reinitiation of Breathing after Neonatal Resuscitation in Rat Pups. Pediatric Research. 2007; 61: 698–702.

IMMATURITY OF THE CNS

¢ Immaturity of pre-term brain present in histologic samples

¢ Fewer synaptic connections

¢ Paucity of myelin

¢ Less dendritic arborization

¢ Auditory evoked responses impaired in preterm infants with AOP

INHIBITORY NEUROTRANSMITTERS

¢ Increased presence and activity of inhibitory neural pathways and neurotransmitters

¢ GABA¢ Major inhibitory neurotransmitter

¢ Increased number of GABA-A receptors in early post-natal life¢ Implicated in hypoxic ventilatory depression

¢ Adenosine¢ Depresses neural function and respiration

¢ Indirect evidence for role in AOP from animal studies

¢ Methylxanthines are competitive antagonists at the adenosine receptor

UPPER AIRWAY COLLAPSE

¢ Upper airway obstruction is a prominent component of AOP

¢ Delay in activation of tone-maintaining airway musculature during hypercapneic episodes

¢ Theoretical ‘overactive’ vagal inhibition of airway dilator muscles

UPPER AIRWAY COLLAPSE

MANAGEMENT OF AOP - METHYLXANTHINES

¢ Mainstay of therapy for AOP since the 1970s¢ Studies showed decrease in apnea frequency when on theophylline

and caffeine

¢ Competitive antagonist at adenosine receptors

¢ Initial concerns about safety

¢ Increased metabolic demand and impact on growth

¢ Adenosine as a neuroprotective agent in hypoxia

MANAGEMENT OF AOP – THE CAP TRIAL

¢ The CAP Trial¢ Large, multi-center RCT comparing caffeine to placebo

¢ Originally designed to evaluate safety

¢ Published follow-up at discharge, 18 months, and 5 years

¢ Initial results at hospital discharge¢ Decreased GA at last extubation and cessation of PPV

¢ Decreased rates of BPD

¢ Slower weight gain in 3 weeks after therapy initiated

Schmidt B et al. Caffeine therapy for apnea of prematurity.N Engl J Med. 2006;354(20):2112-21.

.

MANAGEMENT OF AOP – THE CAP TRIAL

Schmidt B et al. Long-Term Effects of Caffeine Therapy for Apnea of Prematurity. N Engl J Med. 2007; 357:1893-1902

MANAGEMENT OF AOP – THE CAP TRIAL

Schmidt B et al. Survival Without Disability to Age 5 Years After Neonatal Caffeine Therapy for Apnea of Prematurity. JAMA. 2012;307(3):275-282.

MANAGEMENT OF AOP – THE CAP TRIAL

Schmidt B et al. Survival Without Disability to Age 5 Years After Neonatal Caffeine Therapy for Apnea of Prematurity. JAMA. 2012;307(3):275-282.

MANAGEMENT OF AOP - CPAP

¢ Provides distending pressure in airway¢ May prevent upper airway collapse and obstruction

¢ Improves oxygenation¢ May blunt hypoxic ventilatory depression

MANAGEMENT OF AOP - CPAP

Miller MJ et al. Continuous positive airway pressure selectively reduces obstructive apnea in preterm infants. The Journal of Pediatrics. 1985; 106 (1): 91 – 94.

APNEA AND GASTROESOPHAGEAL REFLUXTHE CONTINUED CONTROVERSY

¢ Postulated link between apnea GER in pre-term infant

¢ Rate of GER is high in pre-term infants

¢ Physiologic mechanism via laryngeal chemoreflex

¢ Many studies over decades with inconsistent results

APNEA AND GERTHE CONTINUED CONTROVERSY

Barrington J et al. Apnea at Discharge and Gastro-Esophageal Reflux in the Preterm Infant. Journal of Perinatology. 2002; 22:8 – 11.

APNEA AND GER IN PRETERM INFANTS

Barrington J et al. Apnea at Discharge and Gastro-Esophageal Reflux in the Preterm Infant. Journal of Perinatology. 2002; 22:8 – 11.

APNEA AND GER IN PRETERM INFANTS

Corvaglia L et al. Gastro-Oesophageal Reflux Increases the Number of Apnoeas in Very Preterm Infants. Arch Dis Child Fetal Neonatal Ed. 2008; 94 (3): F188-F192.

APNEA AND GER IN PRETERM INFANTS

Di Fiore J et al. Characterization of Cardiorespiratory Events following Gastroesophageal Reflux (GER) in Preterm Infants. J Perinatol. 2010 October ; 30(10): 683-687

LONG-TERM OUTCOMES OF AOP

¢ Long-term risks of AOP are unclear¢ Difficult to separate from

other comorbid problems

¢ Particularly confounded by BPD/CLD

LONG-TERM OUTCOMES OF AOP

AOP AND NEURODEVELOPMENT

Pillekamp F et al. Factors Influencing Apnea and Bradycardia of Prematurity –Implications for Neurodevelopment. Neonatology. 2007;91:155-161

¢ Prolonged AOP is correlated with more severe neurodevelopmental handicaps

AOP AND RECEPTIVE LANGUAGE

Greene J et al. Cardiorespiratory events in extremely low birth weight infants: neurodevelopmental outcome at 1 and 2 years. Journal of Perinatology. 2014; 34:562–565

¢ 2014 retrospective chart review of ELBW babies with AOP¢ Followed at 8 and 20 months

¢ Frequency of AOP was related to worse language scores at 8 months

¢ Severity of AOP related to worse language at 20 months CA

SUMMARY

¢ Apnea is a symptom, not a diagnosis

¢ New onset apnea requires thoughtful evaluation

¢ Respiratory control relies on complex interplay of central and peripheral receptors and reflexes

¢ Abnormal in the neonate

¢ Caffeine and CPAP are both effective therapies for AOP

¢ Caffeine improves neurodevelopmental outcomes

¢ The link between AOP and GER remains controversial

¢ Most studies suggest no benefit to reflux and promotility medications

THANK YOU. QUESTIONS?

RESPIRATORY CENTER NEUROANATOMY

PERIPHERAL CHEMORECEPTORS

In utero – carotid receptor sensitivity to O2 is adapted to

low PaO2.

At birth – fourfold increase in PaO2

Postnatal Hyperoxia

Decrease in peripheral

chemosensitivity

Decreased respiratory drive

Postnatal hypoxia

Increased peripheral

chemosensitivity

APNEA AND RESPONSE TO HYPEROXIC TEST

Cardot, Pediatric Res 2007

PATHOGENESIS

SEPSIS

Hofstetter, PNAS 2007

EFFECT OF LPS ON MINUTE VENTILATION DURING EXPOSURE TO 10%FIO2 IN RATS

Balan, Resp Physiology and Neurobiology, 2011

Di Fiore, J of Pediatrics, 2010

Di Fiore, J of Pediatrics, 2010

MANAGEMENT OF AOP – THE CAP TRIAL

Schmidt B et al. Long-Term Effects of Caffeine Therapy for Apnea of Prematurity. N Engl J Med. 2007; 357:1893-1902